Interplay Between Epigenetic and Genetic Alterations in Inborn Errors of Immunity

Overview

Journal Trends Immunol

Specialty Allergy & Immunology

Date 2023 Oct 9

PMID 37813732

Authors

Javier Rodriguez-Ubreva

Celia L Calvillo

Lisa R Forbes Satter

Esteban Ballestar

Affiliations

Soon will be listed here.

Abstract

Inborn errors of immunity (IEIs) comprise a variety of immune conditions leading to infections, autoimmunity, allergy, and cancer. Some IEIs have no identified mutation(s), while others with identical mutations can display heterogeneous presentations. These observations suggest the involvement of epigenetic mechanisms. Epigenetic alterations can arise from downstream activation of cellular pathways through both extracellular stimulation and genetic-associated changes, impacting epigenetic enzymes or their interactors. Therefore, we posit that epigenetic alterations and genetic defects do not exclude each other as a disease-causing etiology. In this opinion, encompassing both basic and clinical viewpoints, we focus on selected IEIs with mutations in transcription factors that interact with epigenetic enzymes. The intricate interplay between these factors offers insights into genetic and epigenetic mechanisms in IEIs.

Citing Articles

Dysregulation of epigenetic modifications in inborn errors of immunity.

Xiao Z, He R, Zhao Z, Chen T, Ying Z Epigenomics. 2024; 16(19-20):1301-1313.

PMID: 39404224 PMC: 11534118. DOI: 10.1080/17501911.2024.2410695.

Immunogenetic Landscape in Pediatric Common Variable Immunodeficiency.

Szczawinska-Poplonyk A, Ciesielska W, Konarczak M, Opanowski J, Orska A, Wroblewska J Int J Mol Sci. 2024; 25(18).

PMID: 39337487 PMC: 11432681. DOI: 10.3390/ijms25189999.

Genetic causes of primary immunodeficiency in the Jordanian population.

Obeidat L, Abu-Halaweh M, Alzyoud R, Albsoul E, Zaravinos A Biomed Rep. 2024; 21(5):160.

PMID: 39268404 PMC: 11391178. DOI: 10.3892/br.2024.1848.

References

Xin J, Zhang Z, Su X, Wang L, Zhang Y, Yang R . Epigenetic Component p66a Modulates Myeloid-Derived Suppressor Cells by Modifying STAT3. J Immunol. 2017; 198(7):2712-2720. DOI: 10.4049/jimmunol.1601712. View

Zhang L, Xiao X, Arnold P, Li X . Transcriptional and epigenetic regulation of immune tolerance: roles of the NF-κB family members. Cell Mol Immunol. 2019; 16(4):315-323. PMC: 6461939. DOI: 10.1038/s41423-019-0202-8. View

Moens L, Van Eyck L, Jochmans D, Mitera T, Frans G, Bossuyt X . A novel kindred with inherited STAT2 deficiency and severe viral illness. J Allergy Clin Immunol. 2017; 139(6):1995-1997.e9. DOI: 10.1016/j.jaci.2016.10.033. View

Baghdassarian H, Blackstone S, Clay O, Philips R, Matthiasardottir B, Nehrebecky M . Variant and Response to Ruxolitinib in an Autoinflammatory Syndrome. N Engl J Med. 2023; 388(24):2241-2252. PMC: 10392571. DOI: 10.1056/NEJMoa2202318. View

Zhang Q, Wang H, Marzec M, Raghunath P, Nagasawa T, Wasik M . STAT3- and DNA methyltransferase 1-mediated epigenetic silencing of SHP-1 tyrosine phosphatase tumor suppressor gene in malignant T lymphocytes. Proc Natl Acad Sci U S A. 2005; 102(19):6948-53. PMC: 1100783. DOI: 10.1073/pnas.0501959102. View

Edwards E, Bosco J, Ojaimi S, OHehir R, van Zelm M . Beyond monogenetic rare variants: tackling the low rate of genetic diagnoses in predominantly antibody deficiency. Cell Mol Immunol. 2020; 18(3):588-603. PMC: 8027216. DOI: 10.1038/s41423-020-00520-8. View

Cross N, Hoade Y, Tapper W, Carreno-Tarragona G, Fanelli T, Jawhar M . Recurrent activating STAT5B N642H mutation in myeloid neoplasms with eosinophilia. Leukemia. 2018; 33(2):415-425. PMC: 6365490. DOI: 10.1038/s41375-018-0342-3. View

Boztug H, Hirschmugl T, Holter W, Lakatos K, Kager L, Trapin D . NF-κB1 Haploinsufficiency Causing Immunodeficiency and EBV-Driven Lymphoproliferation. J Clin Immunol. 2016; 36(6):533-40. PMC: 4940442. DOI: 10.1007/s10875-016-0306-1. View

Gruber C, Calis J, Buta S, Evrony G, Martin J, Uhl S . Complex Autoinflammatory Syndrome Unveils Fundamental Principles of JAK1 Kinase Transcriptional and Biochemical Function. Immunity. 2020; 53(3):672-684.e11. PMC: 7398039. DOI: 10.1016/j.immuni.2020.07.006. View

10.

Rodriguez-Ubreva J, Arutyunyan A, Bonder M, Del Pino-Molina L, Clark S, de la Calle-Fabregat C . Single-cell Atlas of common variable immunodeficiency shows germinal center-associated epigenetic dysregulation in B-cell responses. Nat Commun. 2022; 13(1):1779. PMC: 8975885. DOI: 10.1038/s41467-022-29450-x. View

11.

Fliegauf M, Bryant V, Frede N, Slade C, Woon S, Lehnert K . Haploinsufficiency of the NF-κB1 Subunit p50 in Common Variable Immunodeficiency. Am J Hum Genet. 2015; 97(3):389-403. PMC: 4564940. DOI: 10.1016/j.ajhg.2015.07.008. View

12.

Duncan C, Thompson B, Chen R, Rice G, Gothe F, Young D . Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in . Sci Immunol. 2019; 4(42). PMC: 7115903. DOI: 10.1126/sciimmunol.aav7501. View

13.

Schimke L, Hibbard J, Martinez-Barricarte R, Khan T, Cavalcante R, de Oliveira Junior E . Paracoccidioidomycosis Associated With a Heterozygous STAT4 Mutation and Impaired IFN-γ Immunity. J Infect Dis. 2017; 216(12):1623-1634. DOI: 10.1093/infdis/jix522. View

14.

Cheng F, Lienlaf M, Wang H, Perez-Villarroel P, Lee C, Woan K . A novel role for histone deacetylase 6 in the regulation of the tolerogenic STAT3/IL-10 pathway in APCs. J Immunol. 2014; 193(6):2850-62. PMC: 4157123. DOI: 10.4049/jimmunol.1302778. View

15.

Del Bel K, Ragotte R, Saferali A, Lee S, Vercauteren S, Mostafavi S . JAK1 gain-of-function causes an autosomal dominant immune dysregulatory and hypereosinophilic syndrome. J Allergy Clin Immunol. 2017; 139(6):2016-2020.e5. DOI: 10.1016/j.jaci.2016.12.957. View

16.

Sic H, Speletas M, Cornacchione V, Seidl M, Beibel M, Linghu B . An Activating Janus Kinase-3 Mutation Is Associated with Cytotoxic T Lymphocyte Antigen-4-Dependent Immune Dysregulation Syndrome. Front Immunol. 2018; 8:1824. PMC: 5770691. DOI: 10.3389/fimmu.2017.01824. View

17.

Lee S, Kim J, Min H, Seong R . RORγt-driven T17 Cell Differentiation Requires Epigenetic Control by the Swi/Snf Chromatin Remodeling Complex. iScience. 2020; 23(5):101106. PMC: 7235640. DOI: 10.1016/j.isci.2020.101106. View

18.

Liu Y, Mayo M, Nagji A, Smith P, Ramsey C, Li D . Phosphorylation of RelA/p65 promotes DNMT-1 recruitment to chromatin and represses transcription of the tumor metastasis suppressor gene BRMS1. Oncogene. 2011; 31(9):1143-54. PMC: 3219802. DOI: 10.1038/onc.2011.308. View

19.

Catala-Moll F, Ferrete-Bonastre A, Godoy-Tena G, Morante-Palacios O, Ciudad L, Barbera L . Vitamin D receptor, STAT3, and TET2 cooperate to establish tolerogenesis. Cell Rep. 2022; 38(3):110244. DOI: 10.1016/j.celrep.2021.110244. View

20.

Lv G, Sun G, Wu P, Du X, Zeng T, Wen W . Novel mutations of TYK2 leading to divergent clinical phenotypes. Pediatr Allergy Immunol. 2021; 33(1):e13671. DOI: 10.1111/pai.13671. View